Dysfunctional Uterine Bleeding: An Obsolete Diagnostic Term

Dysfunctional uterine bleeding is a traditional term that was used for years to refer to excessive uterine bleeding in cases where no uterine pathology could be identified.⁴ However, the development of a greater understanding of AUB and the continuing development of more sophisticated diagnostic techniques has made this term outdated.

In most cases, bleeding unrelated to uterine pathology can be determined to be due to chronic anovulation (polycystic ovary syndrome and related conditions), exogenous steroid hormones (contraceptives or hormone replacement therapy), or hemostatic disorders (e.g., von Willebrand’s disease). In many cases that would have been referred to as dysfunctional uterine bleeding in the past, modern diagnostic techniques identify uterine or systemic pathologies that (1) result in anovulation (e.g., hypothyroidism), (2) result from anovulation (e.g., endometrial hyperplasia or cancer), or (3) coexist with anovulatory bleeding but may or may not be causal (e.g., leiomyomata).

Clinically, treatment will always be the most effective when specific causes of AUB can be identified. Because grouping widely divergent causes of AUB together in a poorly defined group is unlikely to improve diagnosis or treatment, a national consensus group has recently concluded that dysfunctional uterine bleeding no longer has any usefulness in clinical medicine.⁵

Infection

Infection is a surprisingly common cause of AUB and is often the basis of what appears to be AUB. In obvious cases of pelvic inflammatory disease (see Chapter 33), approximately 40% of the patients will present with vaginal bleeding.⁹ An underrecognized cause of uterine bleeding is endometritis. Although chronic endometritis was classically diagnosed only when plasma cells were found on endometrial biopsy, recent studies have found an association between AUB and reactive changes in the surface endometrium, but no association with the presence of a particular type of inflammatory cell.¹⁰ Other studies have verified that subclinical endometritis is a common finding in patients diagnosed with AUB and can be related to any of a number of pathogens.¹¹

Cervicitis is another common cause of AUB characterized by postcoital spotting. In addition to common sexually transmitted diseases (i.e., chlamydia and gonorrhea), other vaginal flora and pathogens can be involved.¹² Postcoital bleeding is the most common presenting symptom in women found to have chlamydia infections.¹³

Neoplasms

AUB can be a marker for gynecologic neoplasms. These neoplasms can be benign (e.g., leiomyoma, endometrial or endocervical polyps) or malignant (e.g., endometrial or cervical carcinoma). Focal intracavitary lesions account for up to 40% of cases of AUB.¹⁴ Ovarian neoplasms can indirectly cause irregular bleeding by interfering with ovulation Some of the most common neoplasms known to cause AUB are reviewed here.

Adenomyosis

Adenomyosis is the benign invasion of endometrium into the myometrium. Microscopic examination of the uterus reveals endometrial glands and stroma deep within the endometrium surrounded by hypertrophic and hyperplastic myometrium. This histopathologic diagnosis is made on careful microscopic evaluation of uterine specimens in more than 60% of hysterectomy specimens.²² Clinically, two thirds of patients with adenomyosis will complain of menorrhagia and dysmenorrhea, and pelvic examination usually reveals a diffusely enlarged and tender uterus.

Diagnostic tests that are suggestive of adenomyosis include transvaginal ultrasonography and magnetic resonance imaging (MRI). The sensitivity for ultrasonography probably approaches 50%, and the sensitivity of MRI ranges from 80% to 100%.^22,23 Hopefully, more effective diagnostic tests and treatment besides hysterectomy will be developed in the future.

Hormone Contraceptives

Today, approximately 10 million women in the United States use some type of hormonal contraception, including combination oral contraceptives, progestin-only pills, depot medroxyprogesterone acetate injections, progestin-containing intrauterine devices, subdermal levonorgestrel implants, transdermal combination hormone patches, and intravaginal rings (see Chapter 26). In addition to being a common reason to visit primary care physicians, AUB is a major cause of contraception discontinuation and subsequent unplanned pregnancy.

During the first 3 months of combination oral contraceptive use, as many as one third of women will experience AUB. For the majority of women, the most effective treatment approach is patient reassurance and watchful waiting. As the uterus adapts to the new regimen of hormonal exposure, the monthly withdrawal bleeding becomes regular, lighter, and less painful than natural menstruation in most women.

If abnormal bleeding persists beyond 3 months, other common causes should be excluded. In young sexually active women, sexually transmitted diseases should be excluded; in one study, almost one third of women on oral contraceptives who experienced abnormal bleeding were found to have otherwise asymptomatic Chlamydia trachomatis infections.²⁴ If no cause for AUB other than hormonal therapy is found, treatment options include the use of supplemental estrogen and changing to an oral contraceptive with a different formulation with a different progestin or higher estrogen content (see Chapter 26).

Women using progestin-only contraceptives have an even greater risk of continued AUB than those using combined oral contraceptives. Prolonged exposure to progestins results in a microscopic condition sometimes called pseudoatrophy (see Endometrial Atrophy in this chapter). When reassurance is not sufficient, administration of supplemental estrogen during bleeding episodes is sometimes useful.

Hormone Replacement Therapy

Hormone replacement therapy (HRT) after the menopause is a common iatrogenic cause of AUB. Unopposed daily estrogen therapy is associated with the highest rates of irregular bleeding and subsequent discontinuation of therapy.²⁵ The addition of sequential or continuous oral progestins is associated with decreased irregular bleeding and reduced rate of endometrial hyperplasia. Sequential progestins result in the lowest rate of irregular bleeding during the first year of therapy, but the rate for sequential and continuous therapy is similar thereafter.

Each selective estrogen receptor modulator (SERM) is associated with a distinctive risk of AUB, which varies according to their effect on the endometrium. Tamoxifen, the first SERM used clinically as adjuvant treatment for breast cancer, exhibits antiestrogenic activity in the breast but stimulates the endometrium.²⁶ As a result, tamoxifen has an incidence of postmenopausal vaginal bleeding similar to unopposed estrogen and likewise increases the risk of endometrial pathology, including endometrial polyps, hyperplasia, and cancer.

Raloxifene, a SERM approved for the prevention of osteoporosis, has little if any estrogenic effect on the uterus, resulting in atrophic endometrium.²⁷ As a result, the risk of vaginal bleeding for women taking raloxifene is not increased compared to women not taking any form of HRT.

Normal Menstruation

Each month, the endometrium of normally ovulating women is exposed to physiologic levels of estradiol (50 to 250pg/mL) accompanied for the last 14 days of each cycle by progesterone (midluteal phase <12nmol/L). The result is a structurally stable endometrium 5 to 20mm thick as measured by transvaginal ultrasound.

Withdrawal of progesterone and estrogen results in menstruation, which involves the breakdown and uniform shedding of much of the functional layer of the endometrium, which is enzymatically dissolved by matrix metalloproteinases.²⁸ Normal menses occur every 28±7 days, with duration of flow of 4±2 days and a blood loss of 40±40mL.²⁹ Hemostasis is achieved by a combination of normal coagulation mechanisms and vasoconstriction of the spiral arterioles.

Oligo-ovulation and Anovulation

Irregularity or absence of ovulation is surprisingly common among reproductive-age women not using hormonal contraception. In the perimenarchal years, adolescents often have a number of anovulatory cycles as part of the maturation process, but only occasionally do they complain of clinically significant AUB. In the years immediately preceding menopause, anovulatory cycles again become more common for many women. These episodes of endometrial exposure to unopposed estrogen increase the risk of not only AUB, but also endometrial hyperplasia and endometrial cancer. During the intervening years, both chronic and intermittent intervals of anovulation can occur, often as the result of treatable underlying conditions.

Mechanism of Anovulatory Bleeding

Anovulation results in AUB as a result of chronic exposure of the endometrium to estrogen without the benefit of cyclic exposure to postovulatory progesterone. Endometrium thus exposed to unopposed estrogen becomes abnormally thickened and structurally incompetent. The result is asynchronous shedding of portions of the endometrium unaccompanied by vasoconstriction.

The bleeding associated with unopposed estrogen exposure is often heavy. Because the blood has not been lysed by endometrial enzymes, blood clots are often passed, resulting in increased menstrual cramping in many women. Prolonged periods of bleeding also appear to predispose to subclinical endometritis, which exacerbates bleeding further and is often unresponsive to hormonal therapy.

Polycystic Ovary Syndrome

The most common causes of chronic anovulation are grouped together under a constellation of symptoms referred to as polycystic ovary syndrome (PCOS) (see Chapter 15). PCOS is a heterogeneous endocrine and metabolic disorder that affects 6% to 10% of reproductive-age women.³⁰ This syndrome is diagnosed when a woman without an underlying condition is found to have two out of the following three criteria: (1) oligo-ovulation or anovulation, (2) hyperandrogenism and/or hyperandrogenemia, and (3) polycystic ovaries.³¹ These women have circulating estrogen levels in the normal range but anovulatory progesterone levels.

Polycystic ovary syndrome is often the result of insulin resistance.³⁰ In today’s culture, insulin resistance is often related to obesity. However, not all women with PCOS have insulin resistance and obesity. Insulin resistance is a common but not universal metabolic disorder underlying PCOS.³²

The mechanism whereby insulin resistance results in PCOS is fascinating.³³ Insulin increases production of androgens by both the ovaries (primarily androstenedione and testosterone) and adrenal gland (primarily dihydroepiandrosterone). In the ovary, insulin increases androgen secretion by thecal cells in an LH-dependent process and ovarian stroma cells. These increased androgens contribute to the hirsutism and may contribute to the increased body mass often seen in PCOS patients. These androgens can be aromatized peripherally in both fat and muscle to estrogens (primarily estrone), which acts on the pituitary to increase secretion of LH, which in turn stimulates the ovaries to secrete more androgens in concert with insulin. The resulting positive feedback loop is believed to be the cause of many cases of PCOS. The accuracy of this interpretation is supported by the observation that in many overweight patients, either weight loss or the use of an insulin-sensitizing agent (e.g., metformin) will simultaneously improve insulin resistance and restore regular ovulatory cycles.³³

Systemic Diseases That Can Mimic PCOS

Some patients who are oligo-ovulatory or anovulatory have an underlying systemic disease, and these patients can be clinically indistinguishable from PCOS. Although some diseases can be detected with appropriate testing, not all of these systemic conditions can be treated such that the symptoms of PCOS completely resolve.

Conditions that can result in signs and symptoms identical to PCOS can be divided into two groups. The first group includes conditions that cause hyperandrogenemia, which can in turn interfere with ovulation and result in a clinical picture identical to PCOS.³⁴ These include adult-onset congenital adrenal hyperplasia, Cushing’s syndrome and disease, and androgen-secreting neoplasms of the ovary or adrenal gland. Adult-onset congenital adrenal hyperplasia should be suspected whenever PCOS symptoms occur simultaneously with menarche. Cushing’s and androgen-secreting tumors should be suspected when hyperandrogenism and ovulation dysfunction present rapidly in a woman with previously normal menstrual cycles. Evaluation and management of these specific syndromes are discussed in Chapters 18 and 22.

The second group consists of any systemic condition that can interrupt ovulation. Both hypothyroidism and hyperprolactinemia are relatively common conditions that may have no symptoms other than interference with ovulation. Simple blood tests can screen for these conditions in the initial evaluation of apparent PCOS. In addition, any serious systemic disease can interfere with ovulation—most notably, renal failure and chronic liver disease. Both of these systemic disorders can affect hemostasis. Patients with serious systemic diseases usually manifest significant symptoms in addition to ovulatory dysfunction and AUB.³⁵

Histology

Histologically, hypoestrogenemia leads to atrophy of both endometrial glands and stroma. Scanty, small glands are seen in dense stroma. The result is thin endometrium less than 5mm thick on transvaginal ultrasonography.

Prolonged exposure to exogenous progestins, with or without estrogen, can also result in endometrial atrophy. Long-term use of combination oral contraceptives results in poorly developed glands lined by a single layer of low columnar to cuboidal cells. Secretory changes are minimal, but stromal decidualization is present; the result is discordance between small inactive glands and decidualized stroma. Numerous granular lymphocytes are often present. Progestin-only contraception results in endometrial atrophy with sparse, narrow glands lined by flattened epithelium in a spindle-cell stroma but no decidual reaction. Women with hyperandrogenemia can develop a similar clinical and histologic picture.

Hereditary Bleeding Disorders

Von Willebrand’s disease and less common disorders of platelet function and fibrinolysis are characterized by excessive menstrual bleeding that begins at menarche and is usually regular. As many as 20% of adolescents who present with menorrhagia significant enough to cause anemia or hospitalization have a bleeding disorder, and thus should undergo an evaluation for coagulopathy. However, it is important to remember that most AUB in this age group is probably due to anovulation.³⁶

The most common bleeding disorder is von Willebrand’s disease, which affects 1% to 2% of the population.³⁷ This hereditary deficiency (or abnormality) of the von Willebrand factor (vWF) results in decreased platelet adherence. Von Willebrand factor interacts with platelets to form a platelet plug. A fibrin clot will then form on this plug. There are three main types of von Willebrand’s disease. The mild form (type 1) is responsible for more than 70% of cases and is an absolute decrease in the protein. The mechanism by which an abnormal factor leads to bleeding at the level of the endometrium is unclear. The vast majority of women with von Willebrand’s disease report AUB, specifically menorrhagia. The prevalence of this disorder in adult women with menorrhagia can range from 7% to 20%. Other inherited conditions include thrombocytopenias and rare clotting factor deficiencies (e.g., factor I, II, V, VII, X, XI, XIII deficiencies).

Acquired Bleeding Disorders

New onset of extremely heavy menses not amenable to hormonal therapy can sometimes be related to acquired bleeding abnormalities causing accelerated platelet destruction, such as idiopathic thrombocytopenic purpura (ITP), hematologic diseases affecting platelet production, such as leukemia, or hematologic diseases affecting platelet function (thrombocytopathies). Other systemic disorders such as sepsis and liver disorders can also cause an acquired hemostatic disorder resulting in bleeding.

Anticoagulant Therapy

Excessive bleeding can sometimes be a significant problem for woman taking anticoagulant therapy, such as warfarin or heparin. Fortunately, most women taking anticoagulants do not have problems with AUB, which is considered to be an adverse reaction to anticoagulant therapy. Life-threatening genital bleeding in women taking anticoagulants is rare but may require emergency hysterectomy.³⁸

Pregnancy

In reproductive-age women, the presence of signs and symptoms of pregnancy is important to ascertain. Current contraceptive methods and past pregnancy history are likewise important.

Characterization of Bleeding

Once pregnancy is excluded, the amount and character of the bleeding is the most important information. Careful, stepwise retrospective questioning will usually give a clear picture of the bleeding pattern over the previous days, months, and even years. In nonemergency cases, the use of a prospective menstrual calendar is an excellent way to document the problem as well as the response to therapy (Fig. 21-1). It is important to determine when the bleeding problems were first noticed, because menorrhagia starting at menarche should alert the clinician to the possibility of an underlying bleeding disorder.

Figure 21-1 Menstrual calendar.

The amount of bleeding is probably the most difficult to determine, because normal or heavy menstrual bleeding can be very subjective. For research purposes, menorrhagia can be defined as a monthly blood loss of more than 80mL on three consecutive menses as measured by the alkali hematin method.³⁹ Unfortunately, this type of accurate evaluation is neither cost-effective nor readily available.

Clinically, menorrhagia can be defined as bleeding on the heaviest day requiring changing soaked sanitary pads or tampons more than once every 2 hours, or using more than one sanitary pad at a time. The presence and size of blood clots passed vaginally is important, because normal menstrual effluent is made up of dissolved endometrium and nonclotting blood. Another objective measure of the problem is the amount of days lost from school or work over the past several months.

Symptoms of Hemostatic Disorders

In adolescents with menorrhagia, it is important to determine any past history of excess bleeding during surgical, dental, or obstetric procedures because this has been found to be predictive of von Willebrand’s disease.⁴⁰ Surprisingly, in this same study epistaxis and easy bruising were not clearly discriminatory symptoms.

Endometrial Biopsy

The incidence of endometrial carcinoma in women between ages 40 and 49 has been reported to be as high as 36 per 100,000.⁴³ The risk after menopause continues to increase. For this reason, once pregnancy has been excluded, an endometrial biopsy should be obtained in all women older than age 40 who present with AUB.

Treatment of Women with Coagulopathy

Women with von Willebrand’s disease who complain of menorrhagia can often be successfully treated with long-term oral contraceptive therapy.⁴³ Other medical treatments used by hematologists for acute episodes include desmopressin acetate, antifibrinolytic agents, and plasma-derived concentrates of vWF.⁴³

Hemodynamic Stabilization

Some patients will present with life-threatening uterine bleeding. Although hemorrhagic shock is uncommon secondary to AUB, critically low hemoglobin levels are not, especially in perimenopausal or postmenopausal women at increased risk for cardiac symptoms secondary to severe anemia. Concurrently with establishing that bleeding is unrelated to pregnancy or an anatomic pathology, the hemodynamically unstable patient should be resuscitated with intravenous fluids and blood replacement as indicated.

Expedient Evaluation

After appropriate laboratory tests (i.e., CBC and β-hCG) have been obtained, the most important part of the initial evaluation is transvaginal ultrasonography. If sonohysterography is attempted, it is important to remember that intrauterine clots are often impossible to differentiate from anatomic lesions such as leiomyoma or polyps. An endometrial biopsy is another important part of the evaluation in all women over age 40 unless an emergency D&C is planned. However, hormonal therapy does not have to be delayed until histologic diagnosis has been made.

Dilation and Curettage

In cases where massive uterine bleeding is life-threatening, D&C is the most expedient way to stop blood flow and determine the existence of endometrial pathology when present. The disadvantage of this surgical approach is risk of anesthesia, which is dependent on the patient’s overall medical condition, and the small surgical risk. Although cost should always be a consideration in modern medicine, the usually fast and effective resolution of bleeding often allows discharge within 24 hours. Thus, the cost of surgery may actually be less than the cost of several days’ hospitalization required for the medical treatment discussed in the following. However, D&C has no long-term therapeutic effect; therefore, long-term treatment must be initiated. In most cases of AUB, medical management can be safely used as the first line of treatment.

Intravenous Estrogen Therapy

In many cases where the bleeding is not dangerously brisk, it can be improved overnight by administration of intravenous conjugated estrogens, 25mg given every 4 hours until bleeding stops. When studied in adolescents, it was found that intravenous conjugated estrogen therapy stopped acute bleeding in 90% of cases.³⁶ Those that do not show signs of improvement in their bleeding within 8 hours required D&C.

This therapy might seem paradoxical for use in anyone who is bleeding because of prolonged unopposed estrogen effect on the endometrium. However, its effectiveness has been demonstrated in a well-designed study. In theory, estrogen acutely decreases uterine bleeding related to asynchronous shedding by stimulating clotting at capillary level and promoting vasoconstriction of spiral vessels.

This therapy is often associated with nausea, and intravenous or oral antiemetics (oral or intravenous promethazine [Phenergan], 10mg) should be given simultaneously.

Oral High-Dose Combined Hormonal Therapy

Once bleeding has slowed to that consistent with heavy menses or less, “taper” therapy with oral contraceptives can be started (Table 21-5). This approach is also ideal for women with heavy bleeding who do not require hospitalization for stabilization and observation. Like the intravenous estrogen therapy, nausea is a common problem with this treatment and should be treated preemptively with oral antiemetics to optimize compliance.

Table 21-5 “Taper” Oral Contraceptive Therapy for Abnormal Uterine Bleeding^*

* Regimen for low-dose (30 mcg ethinyl estradiol), monophasic oral contraceptives

Women at Increased Risk for Cardiovascular Disease or Venous Thrombosis

It is well appreciated that estrogen-containing oral contraceptives are relatively contraindicated in any women at increased risk for cardiovascular disease or venous thrombosis. This includes women with a history of thromboembolic disease and woman over age 35 who have additional risk factors (e.g., cigarette smoking, hypertension, diabetes). Although no studies have been published using short-term, high-dose intravenous or oral estrogen in these patients, at least one case of fatal pulmonary thromboembolism has been reported with intravenous therapy.⁴⁴ Certainly, high-dose estrogen therapy should be used in these patients only if the benefits outweigh the risks.

Endometrial Synchronization

In women with chronic irregular bleeding, it is helpful to synchronize the entire endometrium prior to starting cyclic hormones. This may reduce breakthrough bleeding with subsequent therapy. Two approaches for this can be used. A relatively safe method is the use of the potent progestin medroxyprogesterone in a dose of 10mg/day for a full 14 days. This will usually abate the presenting bleeding episode within 2 to 3 days, and help decrease the endometrial height before withdrawal bleeding. Alternatively, “taper” therapy with oral contraceptives can be used for women presenting with heavy, prolonged bleeding.

The patient should be advised that she might have moderately heavy bleeding within 1 to 2 days of stopping the medroxyprogesterone. Oral contraceptives should be started on the Sunday after this withdrawal bleeding. Iron supplementation should also be started in any patient with anemia. The patient should also be cautioned that occasional breakthrough bleeding is to be expected during the first 3 months of oral contraceptive use or if a pill is missed or taken late.

Subclinical Endometritis

It has been recently observed that the most frequent histologic finding in endometrial biopsies of women with AUB is chronic endometritis.⁴⁵ This suggests that when apparently anovulatory AUB does not respond to progestin withdrawal, subclinical endometritis might be a coexisting disorder that must be addressed.

Although few studies have evaluated the role of subclinical endometritis in AUB, several have suggested a relationship. In one study, 81% of patients with irregular bleeding or vaginal discharge had positive endometrial cultures for Mobiluncus, and treatment with metronidazole resolved their irregular bleeding.⁴⁶ In another study of 100 hysterectomies performed for irregular bleeding or fibroids, 25% of the endometrial cavities were found to harbor organisms, including Gardnerella vaginalis, Enterobacter, and Streptococcus agalactiae.⁴⁷ Finally, a study of college-age women presenting with abnormal bleeding while on oral contraceptives found that 29% were infected with Chlamydia.⁴⁸

Together, these data suggest that subclinical endometrial infections might play a role in many women with AUB. Cervical evaluation for common pathogens (i.e., chlamydia and gonorrhea) followed by specific therapy is important. In women with negative cultures who do not respond to cyclic hormonal therapy, empiric therapy with a broad-spectrum antibiotic (e.g., metronidazole or a cephalosporin) might also be reasonable, although prospective studies remain to be performed.

Ovulation Induction

When fertility is desired, restoration of ovulation is paramount. This can be accomplished in many cases by restoring the hormonal milieu to a more normal state. In the case of hyperprolactinemia, lowering prolactin levels with the use of a dopamine agonist will often result in ovulation and pregnancy (see Chapter 22). In the case of PCOS, recent studies have demonstrated that lowering insulin levels with an insulin-sensitizing drug (e.g., metformin hydrochloride) will often restore ovulation and result in pregnancy in many cases (see Chapter 37).

While waiting for these therapies to result in resumption of ovulation and normal menses, monthly induction of withdrawal bleeding with oral progestin is important to avoid continued AUB. In women not using contraceptives, the use of micronized progesterone (100 to 200mg daily for 14 days) will result in reasonable withdrawal bleeding and be safe should pregnancy occur. For patients who do not resume ovulation with systemic therapy, induction of ovulation is attempted using clomiphene citrate or injectable medications as required (see Chapter 37).

Oral Contraceptives

Combination oral contraceptives have been used for decades to decrease both the duration and amount of menstrual flow and dysmenorrhea.⁴⁹ More recently, it has been found that extending the number of consecutive days of active pills could decrease the annual number of menses, thus minimizing menstrual-related symptoms even further.⁵⁰ A consequence of this is the marketing of extended-cycle oral contraceptives that have 3 months of active pills instead of 3 weeks and thus extend the time between menses, such that the patient only has 4 cycles per year. Unfortunately, this regimen has greater risk of spotting and breakthrough bleeding than those using monthly cycles.

Progestins

Progestins (e.g., 10mg medroxyprogesterone, 200mg micronized progesterone) can be administered daily from day 15 to 26 of each cycle to regulate menses in anovulatory patients. This safe and effective approach has none of the side effects or risks associated with oral estrogens and can be used in women of all ages. Progestins given in this manner also prevent endometrial hyperplasia and cancer. In some women, progestins also result in “premenstrual” symptoms, including mood changes or depression, nausea, breast tenderness, and bloating.

In menorrhagia (ovulatory AUB) luteal phase progestins have been shown to be less effective than other medications, including NSAIDs. Longer courses such as 21 days of therapy may be required.⁵¹ Luteal phase progestin therapy is less effective than tranexamic acid, danazol, or the progesterone-releasing intrauterine system (IUS). Progestin therapy for 21 days of the cycle (e.g., day 5 to day 26) is more effective.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs have long been used to reduce dysmenorrhea as well as the amount of menstrual flow, at least in part by inhibiting prostaglandin synthesis.⁵² Although studies are limited, NSAIDs appear to be an effective way to treat AUB in ovulatory women (menorrhagia). NSAIDs should not be used for women with von Willebrand’s disease or a platelet dysfunction.

GnRH Analogues

Continuous administration of a GnRH antagonist results in increased ovarian stimulation (referred to as a flare) followed in approximately 2 weeks by pituitary down-regulation, hypoestrogenemia, and complete cessation of menses. GnRH antagonists avoid this flare, but have only recently become available and their clinical utility remains to be determined. All GnRH analogues are associated with symptoms of acute estrogen deprivation, most notably hot flashes, and bone loss that is to some degree irreversible after 6 months of use. For these reasons and because of expense, the GnRH analogues are rarely used for long-term treatment of AUB.

Levonorgestrel-Containing Intrauterine System

The levonorgestrel-containing IUS, developed originally for contraception, is effective for the treatment of both menorrhagia and dysmenorrhea (see Chapter 27). The local release of levonorgestrel into the uterine cavity suppresses endometrial growth and has been shown to decrease menstrual blood loss by as much as 97%.⁵³ Although many women complain of intermenstrual bleeding during the first few months of use, as many as 20% will have amenorrhea after a year. Even though the progestins are administered locally, some women complain of systemic side effects, such as breast tenderness. Although the initial cost of the levonorgestrel-containing IUS is high compared to other medical treatment, these devices are now approved for 10 years of uninterrupted use and are thus very cost-effective for long-term therapy.

Danazol

This synthetic derivative of testosterone has been shown to be effective for menorrhagia in doses between 200 and 400mg. However, the androgenic side effects, need for barrier contraception, and the need to take the medication daily for long periods of time limit its use.

Desmopressin

This drug is useful in decreasing bleeding in women with von Willebrand’s disease. It increases factor VIII and vWF. It has several potential routes of administration, such as intravenous, subcutaneous, and intranasal. Its main side effects are vasomotor; potential hyponatremia is associated with its use.

Hormone Replacement Therapy

Some women older than age 40 with ovulatory dysfunction will also complain of symptoms of reduced estrogen production, such as hot flashes or sleep disturbances. Many of these women treated with continuous estrogen and cyclic progestin therapy will obtain symptomatic relief; up to 90% will respond with predictable progesterone withdrawal bleeding.⁵⁴ The potential increased risk of venous thrombosis, cardiovascular disease, and breast cancer should be discussed with the patient.